For therapy of patients whose renal function is impaired, for example, patients whose function of removing waste products or the like in blood is impaired because of renal insufficiency or the like, therapy by blood purification such as hemodialysis or hemodialysis filtration has so far been performed. In this blood purification therapy, urea, creatinine, uric acid, low-molecular proteins, water and the like accumulated in blood are removed by bringing the blood into contact with a dialysate through semipermeable membranes in a dialyzer.
In recent years, a substance that causes amyloidosis, which is one of the complications in dialysis, has been identified as β2 microglobulin having a molecular weight of 11,800 (Gejyo F. et al. Biochem. Biophys. Res. Commun. 1985: 129: 701-706). Since β2 microglobulin having a high molecular weight has a low diffusion rate, removal efficiency is higher by hemofiltration than by hemodialysis. Further, since a substance having a low molecular weight, such as urea, has a high diffusion rate, removal efficiency is higher by hemodialysis than by hemofiltration. Accordingly, a hemodialysis filtration (HDF) therapy, which is a combination of hemodialysis and hemofiltration, has been conceived. In the HDF therapy, filtration of a large amount of blood is conducted with a dialyzer and a replenisher is supplied in a blood circuit. Therefore, an exclusive device with a complicated structure is required.
Meanwhile, a dialyzer excellent in substance permeability and water permeability, which can remove β2 microglobulin having a high molecular weight, has been developed. It has been found that such a dialyzer excellent in substance permeability and water permeability allows filtration and backfiltration between blood and a dialysate via a semipermeable membrane (hereinafter referred to as internal filtration and internal backfiltration) even when forced filtration by dewatering is not performed (U. Bauremeister et al., Nephrol Dial Transplant. Suppl., 1989). Accordingly, a hemodialysis filtration method that performs filtration and replenishment by increasing an amount of internal filtration and an amount of internal backfiltration has been proposed. Additionally, an internal filtration accelerating-type dialyzer capable of increasing dialysis efficiency, which is used in the hemodialysis filtration method, is being developed.
Usually, the internal filtration and the internal backfiltration do not occur at a same position within a dialyzer. Since blood and a dialysate are passed through a dialyzer in directions opposite to each other, a fluid having a higher pressure moves to a fluid having a lower pressure via a semipermeable membrane regarding the blood and the dialysate. That is, there is a tendency that the internal filtration occurs on a blood inflow side within a dialyzer and the internal backfiltration occurs on a blood outflow side within a dialyzer.
For increasing an internal filtration rate and an internal backfiltration rate in a dialyzer, it is necessary to increase a pressure loss along a blood flow path or a dialysate flow path. The pressure loss along the flow path is represented by the Hagen-Posuille formula which is a pressure loss inducing formula of a laminar flow in a cylindrical tube:ΔP=8μLQ/ΠR4                 (ΔP: pressure loss along a flow path, μ: viscosity of a fluid, L: length of a flow path, R: radius of a flow path, Q: volume flow rate).        
It is found that to increase the pressure loss ΔP along the flow path, the volume flow rate Q may be increased, the cross-sectional area of the flow path ΠR2 may be decreased, or the length L of the flow path may be increased.
For increasing an internal filtration rate and an internal backfiltration rate of a dialyzer, a dialyzer, the length of the flow path of which is increased by increasing total length (Japanese Patent Registration No. 2961481), and a dialyzer, the cross-sectional area of the blood flow path of which is decreased by decreasing the inner diameter of the hollow fiber membrane, (International Patent Application (PCT Pamphlet) WO 98/22161), have so far been known.
However, in the dialyzer with the total length increased, for obtaining effects of sufficient acceleration of internal filtration and internal backfiltration, the length of the flow path has to be increased to more than twice the length of the flow path in an ordinary dialyzer. Such a dialyzer is impractical. Further, in the dialyzer with the inner diameter of the hollow fiber membrane decreased, fluctuations occur in the inner diameter of the hollow fiber membrane during manufacture, which may increase blood remaining in lumens of the hollow fiber membranes after use of the dialyzer.
Further, there has been proposed, as a dialyzer in which a sectional area of a dialysate flow path is decreased by increasing a packing ratio of hollow fiber membranes, a dialyzer in which the hollow fiber bundle having more hollow fibers than ordinary hollow fiber bundles is shrunk with a net or the like and inserted in a case (Japanese Patent Application Laid-open No. Hei 08-168525 or International Patent Application (PCT Pamphlet) WO 98/22161). However, in the dialyzer with the hollow fiber bundle shrunk, the diameter of the hollow fiber bundle has to be decreased more than necessary in order to insert the hollow fiber bundle into a case. Therefore, the hollow fiber membranes might be ruptured and the packing ratio of the hollow fiber membranes inserted into the case is not high enough.
Moreover, as a dialyzer with a decreased cross-sectional area of a dialysate flow path, a dialyzer in which a substance having a property of being swelled with a dialysate is introduced in a dialysate flow path (International Patent Application (PCT Pamphlet) WO 98/22161 or Japanese Patent Application Laid-open No. Hei 08-192031 or Japanese Patent Application Laid-open No. Hei 11-009684), a dialyzer in which a bag-shaped member is introduced into a dialysate flow path and the bag-shaped member is swelled by introducing therein a physiological saline or the like at the time of using the dialyzer (International Patent Application (PCT Pamphlet) WO 98/22161 or Japanese Patent Application Laid-open No. Hei 11-000394 or Japanese Patent Application Laid-open No. Hei 11-319080), a dialyzer in which a hollow fiber bundle can be compressed together with a case with pressure applied from outside the case (Japanese Patent Application Laid-open No. Hei 11-319079) and the like have also been developed.
In a dialyzer in which a substance having a property of being swelled with a dialysate is introduced, the substance having the swelling property itself has a thickness so that an amount of the substance that can be introduced into the dialyzer is limited. When the amount of the substance having the swelling property is large, it is difficult to insert the hollow fiber bundle into the case of the dialyzer. On the other hand, when the amount of the substance having the swelling property is small, the cross-sectional area of the dialysate flow path is not sufficiently lowered. Further, in a dialyzer with the cylindrical substance having a swelling property introduced therein, it is difficult to insert the hollow fiber bundle into the lumen of the substance having the swelling property, because the substance has a far smaller inner diameter than the case, and the hollow fiber membranes might be ruptured. Further, in a dialyzer in which a bag-shaped member is swelled, or in a dialyzer in which a hollow fiber bundle is compressed together with a case, the structure is complicated and a force exerted in swelling the bag-shaped member or a force exerted by compression is also exerted on the case of the dialyzer. Thus, improvement in the case material is required so that the case has a satisfactory rigidity.
Moreover, a dialyzer with a cylindrical elastic tube has also been developed to contact hollow fibers with each other (French Patent Application No.2267138).
However, the elastic tube in this invention tightens a bundle of the hollow fibers and causes the hollow fibers to contact each other to prevent regular irrigation of dialysate. The cross-sectional area of the dialysate flow path cannot be decreased. Therefore the pressure loss along the dialysate flow path cannot be increased by the elastic tube in this invention.
Under these circumstances, an object of the present invention is to provide a dialyzer which can solve the foregoing problems associated with the conventional dialyzers. More specifically, an object of the present invention is to provide a dialyzer which is simple in structure without fear of rupturing hollow fiber membranes during fabrication and in which an internal filtration rate and an internal backfiltration rate are increased by decreasing the cross-sectional area of the dialysate flow path.